PHYSIOLOGY OF AUTONOMIC NERVOUS SYSTEM

PHYSIOLOGY OF AUTONOMIC NERVOUS SYSTEM

 

Morpho-functional organization of autonomic nervous system

a) Sympathetic nervous system (Sympathetic patr of autonomic nervous system includes paravertebral ganglions, prevertebral ganglions, sympathetic nerves. In the lateral parts of the spinal cord on the thoracic-lumbal level are present sympathetic centre of Yakobson, whose activity regulated by brain stem. Axons of neurons of sympathetic centre go out from the spinal cord in ventral roots and form white branches with the ganglions of sympathetic stems. From these stems go out postganglionic axons and go to the organs of brain, thorax, abdominal cavity and pelvis. Preganglionic axons, which goes out on the level of segments of spinal cord, innerevate a few paravertebral and prevertebral ganglions; that is why provide multiplicative central regulation of different visceral functions.

This review examines how the sympathetic nervous system plays a major role in the regulation of cardiovascular function over multiple time scales. This is achieved through differential regulation of sympathetic outflow to a variety of organs. This differential control is a product of the topographical organization of the central nervous system and a myriad of afferent inputs. Together this organization produces sympathetic responses tailored to match stimuli. The long-term control of sympathetic nerve activity (SNA) is an area of considerable interest and involves a variety of mediators acting in a quite distinct fashion. These mediators include arterial baroreflexes, angiotensin II, blood volume and osmolarity, and a host of humoral factors. A key feature of many cardiovascular diseases is increased SNA. However, rather than there being a generalized increase in SNA, it is organ specific, in particular to the heart and kidneys. These increases in regional SNA are associated with increased mortality. Understanding the regulation of organ-specific SNA is likely to offer new targets for drug therapy. There is a need for the research community to develop better animal models and technologies that reflect the disease progression seen in humans. A particular focus is required on models in which SNA is chronically elevated.

Historically, the sympathetic nervous system (SNS) has been taught to legions of medical and science students as one side of the autonomic nervous system, presented as opposing the parasympathetic nervous system. This review examines the evidence that over the past decade a new and more complex picture has emerged of the SNS as a key controller of the cardiovascular system under a variety of situations. Studies have revealed some of the central nervous system pathways underlying sympathetic control and where or how a variety of afferent inputs regulate sympathetic outflow. Our understanding of how sympathetic nerve activity regulates end organ function and blood pressure has increased along with the development of new technologies to directly record SNA in conscious animals and humans. Most importantly, increasing clinical evidence indicates a role for sympathoactivation in the development of cardiovascular diseases. Such information highlights the need to better understand how the SNS interfaces with the cardiovascular system and how this interaction may result in increased morbidity or mortality. Aspects of the SNS have been the subject of reviews in the past, and with between 1,300 and 2,000 publications published per year for the past 5 years involving various aspects of the SNS, it is not possible to cover in detail the wealth of recent information on this area. The accent of this review is on the nature of the activity present in sympathetic nerves, how it affects cardiovascular function, and how it is implicated in disease processes. It aims not to simply catalog the studies surrounding these areas, but rather attempts to distill down observations to provide future directions and pitfalls to be addressed.

SNS activity provides a critical aspect in the control of arterial pressure. By rapidly regulating the level of activity, the degree of vasoconstriction in the blood vessels of many key organs around the body is altered. This in turn increases or decreases blood flow through organs, affecting the function of the organ, peripheral resistance, and arterial pressure. In contrast to the activity present in motor nerves, sympathetic nerves are continuously active so all innervated blood vessels remain under some degree of continuous constriction. Since its first description in the 1930s sympathetic nerve activity (SNA) has engendered itself to researchers in two camps; neurophysiologists have seen its inherent properties as an opportunity to understand how areas of the central nervous system may be “wired” to generate and control such activity, while cardiovascular physiologists saw its regulation of blood flow as a means to measure the response to different stimuli, drugs, and pathological conditions. However, the innervation to almost all arterioles and actions on specific organs such as the heart and kidney is not sufficient to justify its importance. What distinguishes the SNS is the emerging evidence that overactivity is strongly associated with a variety of cardiovascular diseases. A key question is, Does this increased SNA act as a driver of the disease progression or is it merely a follower? Furthermore, how does increased SNA accelerate the disease progression? Is it simply that it results in increased vascular resistance or are there subtle structural changes induced by elevated SNA or specific actions on organs such as the kidney through its regulation of the renin-angiotensin system and/or pressure natriuresis?

It was Walter Cannon who portrayed the SNS as central to the regulation of homeostasis. Cannon showed that when an animal is strongly aroused, the sympathetic division of its autonomic nervous system “mobilizes the animal for an emergency response of flight or fight. The sympathico-adrenal system orchestrates changes in blood supply, sugar availability, and the blood’s clotting capacity in a marshalling of resources keyed to the violent display of energy.” In this setting, the SNS and parasympathetic nervous system were presented as two opposing forces with the parasympathetic endorsing “rest and digest” while the SNS “flight and fight.” An unintended side effect advanced in some textbooks has been to portray the actions of sympathetic nerves as confined to extreme stimuli. As will be advanced in this review, the SNS plays a key role in the moment-to-moment regulation of cardiovascular function at all levels from quiet resting to extreme stimuli. While SNA can be quite low under quiet resting conditions, removal of all sympathetic tone via ganglionic blockade significantly lowers blood pressure. Furthermore, removal of SNA to only one organ such as the kidney can chronically lower blood pressure in some animals, indicating its importance in maintaining normal cardiovascular function.

Evidence that sympathetic nerves are tonically active was established from the 1850s with the observation that section or electrical stimulation of the cervical sympathetic nerve led to changes in blood flow in the rabbit ear. However, it was not until the 1930s that Adrian, Bronk, and Phillips published the first description of actual sympathetic discharges. They observed two obvious features: 1) that discharges occur in a synchronized fashion, with many of the nerves in the bundle being active at approximately the same time, and 2) that discharges generally occur with each cardiac cycle in a highly rhythmical fashion. They also noted that by no means was the overall activity level constant as it was increased by asphyxia or a small fall in blood pressure. This was the first direct evidence supporting Hunt’s assertion in 1899 that “the heart is under the continual influence of sympathetic impulses.” These early studies answered a number of questions on the nature of multifiber discharges, such as whether the activity present in the nerve bundle reflected that of single fibers firing very rapidly, or groups of fibers firing more or less synchronously. They also showed that the synchronized activation of postganglionic nerves was not a function of the ganglia as it could be observed in preganglionic nerves and that activity was bilaterally synchronous, that is, that activity in right and left cardiac nerves was the same.

The origin of the rhythmical discharges was considered in the 1930s to be a simple consequence of phasic input from arterial baroreceptors, which had been shown to display pulsatile activity. This proposal had the effect of diminishing the role of the central nervous system to that of a simple relay station and may go some way to explaining the lack of further interest in recording SNA until the late 1960s. Green and Heffron then reexamined the question of the origin of SNA after noting a rapid sympathetic rhythm (at ∼10 Hz) under certain conditions (mainly reduced baroreceptor afferent traffic) that was far faster than the cardiac rhythm. This indicated that the origin of bursts of SNA could not simply be a product of regular input from baroreceptors. Their suggestion that the fast rhythm did not have a cardiac or ganglionic origin, but was of brain stem origin, stimulated interest from neurophysiologists, who could use this phenomena for the study of the central nervous system.

Postganglionic sympathetic nerves are composed of hundreds to thousands of unmyelinated fibers, whose individual contributions to the recorded signal are exceedingly small. But fortunately, their ongoing activity can be measured from whole nerve recordings because large numbers of fibers fire action potentials at almost the same time (synchronization) to give discharges of summed spikes. Although it is possible to perform single unit recordings from postganglionic nerve fibers, the favored approach is a multiunit recording. This is obviously a much easier experimental preparation, which allows recordings in conscious animals. However, several important points can only be shown from single-unit recordings. First, while multifiber discharges can occur at quite fast rates (up to 10 Hz), the frequency of firing in the single unit is much lower. Average rates in anesthetized rabbits have been recorded between 2 and 2.5 spikes/s for renal nerves, ∼1.2 spikes/s for splenic nerves in the cat, and between 0.21 and 0.5 spikes/s in the human. This slow firing rate means that the rhythmical properties of the single-unit discharges are not seen unless their activity is averaged over time against a reference such as the cardiac cycle or respiration. Single unit recordings also show the minimal firing interval for postganglionic neurons is between 90–100 ms. This indicates it is unlikely that multifiber discharges represent high frequency impulses from a single neuron, but rather the summation of impulses from multiple fibers that fire synchronously. These properties have subsequently been confirmed with single unit recordings in the human. The low firing rate of individual nerves seems to preclude the same neuron being activated more than once in each multifiber discharge. Rather, it would seem that the activated neurons are drawn from a neuronal pool. It is unlikely that the low firing rate is due to a long refractory period for the nerves, since the individual nerves can be induced to fire at quite fast rates by stimuli such as from chemoreceptors or nociceptors.

b) Parasympathetic nervous system (Parasympathetic patr of autonomic nervous system includes ganglions (present near organs-effectors or inside them), parasympathetic nerves. Bodies of the preganglionic parasympathetic neurons are in the brain stem and in the sacral level of spinal cord. Axons of preganglioeurons go to the postganglion neurons, which are present in ganglions. The parasympathetic fibers are in n.oculomotorius, n.facialis, n.glossopharyngeus, n.vagus, sacral nerves. Parasympathetic nervous system also innervates muscles of vessels, exept sex organs and may be brain.)

c) Metasympathetic nervous system (Metasympathetic patr of autonomic nervous system is intramural ganglions, which are in the organs walls. Reflector arc are present in the wall of organs too. It regulated by sympathetic and parasympathetic system. It has sensory, interneuronal, moving chain and own mediators.)

The autonomic nervous system, like the somatic nervous system, is organized on the basis of the reflex arch. Impulses initiated in visceral receptors are relayed via afferent autonomic pathways to the central nervous system, integrated within it at various levels, and transmitted via efferent pathways to visceral effectors.

The ANS is further divided into the sympathetic nervous system and the parasympathetic nervous system. Both of these systems can stimulate and inhibit effectors. However, the two systems work in opposition—where one system stimulates an organ, the other inhibits. Working in this fashion, each system prepares the body for a different kind of situation, as follows.

·                     The sympathetic nervous system prepares the body for situations requiring alertness or strength or situations that arouse fear, anger, excitement, or embarrassment (“fight-or-flight” situations). In these kinds of situations, the sympathetic nervous system stimulates cardiac muscles to increase the heart rate, causes dilation of the bronchioles of the lungs (increasing oxygen intake), and causes dilation of blood vessels that supply the heart and skeletal muscles (increasing blood supply). The adrenal medulla is stimulated to release epinephrine (adrenalin) and norepinephrine (noradrenalin), which in turn increases the metabolic rate of cells and stimulate the liver to release glucose into the blood. Sweat glands are stimulated to produce sweat. In addition, the sympathetic nervous system reduces the activity of various “tranquil” body functions, such as digestion and kidney functioning.

·                     The parasympathetic nervous system is active during periods of digestion and rest. It stimulates the production of digestive enzymes and stimulates the processes of digestion, urination, and defecation. It reduces blood pressure and heart and respiratory rates and conserves energy through relaxation and rest.

In the SNS, a single motor neuron connects the CNS to its target skeletal muscle. In the ANS, the connection between the CNS and its effector consists of two neurons—the preganglionic neuron and the postganglionic neuron. The synapse between these two neurons lies outside the CNS, in an autonomic ganglion. The axon (preganglionic axon) of a preganglionic neuron enters the ganglion and forms a synapse with the dendrites of the postganglionic neuron emerges from the ganglion and travels to the target organ. There are three kinds of autonomic ganglia:

·                     The sympathetic trunk, or chain, contains sympathetic ganglia called paravertebral ganglia. There are two trunks, one on either side of the vertebral column along its entire length. Each trunk consists of ganglia connected by fibers, like a string of beads.

·                     The prevertebral (collateral) ganglia also consist of sympathetic ganglia. Preganglionic sympathetic fibers that pass through the sympathetic trunk (without forming a synapse with a postganglionic neuron) synapse here. Prevertebral ganglia lie near the large abdominal arteries, which the preganglionic fibers target.

·                     Terminal (intramural) ganglia receive parasympathetic fibers. These ganglia occur near or within the target organ of the respective postganglionic fiber.

A comparison of the sympathetic and parasympathetic pathways follows (see Figure 2 ):

·                     Sympathetic nervous system. Cell bodies of the preganglionic neurons occur in the lateral horns of gray matter of the 12 thoracic and first 2 lumbar segments of the spinal cord. (For this reason, the sympathetic system is also called the thoracolumbar division.) Preganglionic fibers leave the spinal cord within spinal nerves through the ventral roots (together with the PNS motor neurons). The preganglionic fibers then branch away from the nerve through white rami (white rami communicantes) that connect with the sympathetic trunk. White rami are white because they contain myelinated fibers. A preganglionic fiber that enters the trunk may synapse in the first ganglion it enters, travel up or down the trunk to synapse with another ganglion, or pass through the trunk and synapse outside the trunk. Postganglionic fibers that originate in ganglia within the sympathetic trunk leave the trunk through gray rami (gray rami communicantes) and return to the spinal nerve, which is followed until it reaches its target organ. Gray rami are gray because they contain unmyelinated fibers.

·                     Parasympathetic nervous system. Cell bodies of the preganglionic neurons occur in the gray matter of sacral segments S₂-S₄ and in the brain stem (with motor neurons of their associated cranial nerves III, VII, IX, and X). (For this reason, the parasympathetic system is also called the craniosacral division, and the fibers arising from this division are called the cranial outflow or the sacral outflow, depending upon their origin.) Preganglionic fibers of the cranial outflow accompany the PNS motor neurons of cranial nerves and have terminal ganglia that lie near the target organ. Preganglionic fibers of the sacral outflow accompany the PNS motor neurons of spinal nerves. These nerves emerge through the ventral roots of the spinal cord and have terminal ganglia that lie near the target organ.

VIDEO

Vegetative functions are those bodily processes most directly concerned with maintenance of life. This category encompasses nutritional, metabolic, and endocrine functions including eating, sleeping, menstruation, bowel function, bladder activity, and sexual performance. These functions can be altered by a wide variety of psychologic states.

Problems in vegetative function are so frequent that every patient with an emotional disorder should be asked about disturbances in food intake, elimination, menstruation, and sleep. What the clinician primarily investigates is a psychologically induced change, which may be either increased or decreased, in the patient’s usual pattern.

By the time questions related to vegetative function are explored, the physician will have already sought for evidence of anxiety, depression, or interpersonal difficulties in other parts of the psychiatric database. Then the physician determines whether there is an association between the vegetative function disturbances and emotional conflicts. In doing this, it is helpful to ask such questions as the following: “Did the bodily disturbance (e.g., anorexia) begin during a time of emotional stress? Does it become worse when emotional stress increases? Does it vary in different situations?”

With the exception of the sexual area, most patients do not find it difficult to discuss problems related to their vegetative functions. Almost everyone has experienced disturbances in these bodily functions at some time, and there is little or no stigma attached to admitting to these difficulties. There is usually a temporal and a quantifiable relationship between the emotional symptoms and disturbance in vegetative function. Increase or decrease in emotional symptoms is often accompanied by concomitant changes in the disturbance of vegetative function. Characteristically, increased emotional stress is associated with increased vegetative dysfunction.

It is also important when exploring this area to ask in a general way about any disturbances of physical function for which past physicians could find no cause. The patient can be asked: “Have you ever had any physical problem for which your physician could find no cause?” The patient could also be asked: “Have you ever been told that you were having physical symptoms as a result of nervousness, depression, or stress?”

It is important to ask patients specifically about the presence of any eating disorders, such as anorexia nervosa or bulimia, both of which are discussed later in this chapter. Patients with either disorder are often very secretive. They will almost never volunteer any information regarding their symptoms. Nevertheless, when asked directly about binge eating, self-induced vomiting, or use of cathartics or diuretics in order to lose weight, many patients will admit to these activities. In addition, the physician should always be alert for the possibility of anorexia nervosa in any female patient who appears emaciated.

The early work of investigators Flanders Dunbar, Franz Alexander, W. B. Cannon, Hans Selye, and others have provided validation of the concept that emotional conflicts can result in changes in physical function. Efforts to link specific personality types or specific psychological conflicts with specific psychophysiological disorders have been attempted many times. For example, the type A personality has been described as being particularly prone to coronary occlusion. The type A personality is typically competitive, restless, and preoccupied with time. Such individuals characteristically also have physiologic findings that include high plasma triglycerides, hyperinsulinemic response to glucose challenge, increased blood cholesterol levels, and increased levels of norepinephrine in urine. Despite the fact that many patients with coronary artery disease appear to fit the type A personality, many patients with coronary artery disease do not fit this personality type. While it seems reasonable on the basis of current investigations to view patients who have a type A personality as being more prone to coronary disease, it also seems clear that this is by no means the entire explanation for this condition.

John Nemiah and Peter Sifneos (1970) have postulated the interesting concept of alexithymia. Alexithymia refers to the condition of being unable to express feeling tones verbally. In this hypothesis, psychosomatic symptoms are developed as an alternative expression of affect as a result of the inability to express and deal with feelings verbally.

Modereurologic research has made it much easier to understand how emotional conflicts can result in changes in vegetative function. Many of the neuronal circuits controlling emotions are centered in the limbic system of the brain. The limbic system has many pathways connecting to autonomic centers in the hypothalamus. When emotional stress leads to increased limbic system activity, there are ample neuronal connections for transmission of this increased activity into hypothalamic areas that control autonomic function. Changes in the output of these autonomic centers pass through the autonomic nervous system to end organs such as the bowel and bladder. Presumably asthma, hypertension, peptic ulcer, and other psychophysiologic disorders are the result, at least in part, of long-continued overactivity of the autonomic nervous system on the various end organs.

The extent to which usual vegetative function is disrupted by emotional conflict allows the clinician to make a rough judgment of the severity of the emotional disturbance. A psychiatric condition in which there is an accompanying disturbance in vegetative function is in general more severe than the same condition without such a bodily disturbance. The presence of a distinct change in vegetative function is of more significance than the direction of the change, since patients with the same emotional symptoms may show opposite changes in bodily function. For example, most depressed patients have decreased appetite, but some such patients overeat, as is described below.

Disturbances in the following areas of vegetative function are of particular significance:

·                    Appetite

·                    Sleep

·                    Menstruation

·                    Bowel habits

·                    Bladder function

·                    Sexual performance

Food is of strong emotional significance. Infants are repeatedly comforted by being offered food. Many people associate the process of eating with feelings of security, comfort, and happiness. For some, eating can become a means of alleviating mild anxiety or depression. This tendency to eat in response to stress is thought to be a factor in some cases of obesity. Although some patients react to depression by overeating, these are usually those in whom depression is mild. The majority of patients with significant depression have a distinct loss of appetite. In a somewhat similar way, an occasional patient with anxiety may react by increasing food consumption. The large majority of patients with moderate to severe anxiety have some degree of decrease in appetite, although characteristically this is not as marked as is seen in depression.

Anorexia nervosa is a particularly important disturbance of eating. Patients with this condition have an intense fear of becoming obese, and this fear does not subside as weight loss progresses. Unless adequately treated, the persistent refusal of these patients to eat may lead to death from complications of starvation. Bulimia is another eating disorder that is of clinical importance. Bulimia refers to the condition in which patients experience recurrent episodes during which large amounts of food are consumed in a short period of time. These episodes are typically referred to as binges. Patients with bulimia frequently terminate the episodes with self-induced vomiting. Patients with either anorexia nervosa or bulimia may use cathartics or diuretics in an effort to lose weight. More than 90% of patients with anorexia nervosa are female, as are a large majority of patients with bulimia. Although fatalities occur less often from bulimia than from anorexia nervosa, serious medical complications can result from bulimia, including esophagitis, dental damage, and toxicity from use of cathartics or diuretics.

Disturbances in sleep involve difficulties in getting to sleep, staying asleep, and in quality of sleep. Difficulty falling asleep occurs in many patients who have either anxiety or depression. A pattern of insomnia that occurs primarily in depression is one in which the patient is able to fall asleep but awakens after a few hours and then is unable to return to sleep. Many patients with emotional conflicts are troubled by disturbing dreams. Such patients often complain of feeling very tired when they awaken in the morning. Some patients respond to emotional stress by withdrawal. The clinician should remember that one form of withdrawal can be sleep. A minority of such patients, much more frequently depressed patients than anxious ones, will sleep excessively.

In the presence of marked emotional stress, female patients not infrequently show a change in their menstrual pattern. Menstrual abnormalities occur in several psychiatric conditions. Patients with marked depression often show a decrease in menstruation that may progress to cessation of menstruation. Amenorrhea also occurs in anorexia nervosa. In these patients, the amenorrhea is usually secondary to starvation. Amenorrhea also occurs in pseudocyesis, which is a condition of false pregnancy found in certain women who have psychologic conflicts around an intense desire to become pregnant.

Changes in bowel habits are frequent in emotional disturbances. Diarrhea often occurs during anxiety states. Constipation frequently accompanies depression.

Disturbances of genitourinary function are infrequent in depression. However, the presence of anxiety is often manifest by increased frequency of urination.

Sexual performance is strongly influenced by emotional stress. Impotence or frigidity are frequent complaints in states of anxiety and in depression. Resolution of emotional conflicts will frequently return sexual performance to normal

 

Regulation of the internal environment of the body with regard to temperature and body fluids is a normal function of the autonomic system. Emotional states are supported by very extensive bodily changes. A state of fear can induce the desire to run, but one cannot run far unless physiological adjustments support the effort. Anger can mean that one is prepared to fight, but it will not be an efficient battle unless one’s circulatory system makes necessary adjustments to provide strength and endurance for the contest. The situatioeed not be a highly emotional one; work and exercise are supported by the same physical adjustments.

Physical adjustments to an emergency are largely controlled by the autonomic nervous system. Preparations to strengthen the body for a critical situation include acceleration and strengthening of the heartbeat, a rise in blood pressure, release of glucose from the liver, and the secretion of a small amount of epinephrine by the adrenal glands. Breathing is made easier by the relaxation of muscles in the bronchial tubes. During an emergency digestion can wait, and so the activity of the digestive system is altered and depressed; the blood supply is largely diverted from the digestive system to the skeletal muscles. These effects are obtained mainly by the stimulation of one division of the autonomic nervous system, the sympathetic, or thoracolumbar, portion.

The autonomic system is divided somewhat artificially into a thoracolumbar, or sympathetic, portion and a craniosacral, or parasympathetic, part. The thoracolumbar division is composed of a chain of ganglia and nerves on either side of the spinal cord, extending from the cervical region through the thoracic and lumbar regions. Throughout the thoracic and lumbar regions each ganglion Is connected to a spinal nerve by a communicating branch. Fibers extend upward to the head from (he superior cervical ganglion; they also extend downward from sacral ganglia, thus increasing the distribution of sympathetic fibers.

The craniosacral, or parasympathetic, division is associated with certain cranial and sacral nerves and will be discussed later. The terms thoracolumbar or craniosacral appear well adapted for anatomical considerations; the terms sympathetic and parasympathetic seem better adapted when referring to the physiology of the autonomic system.

Anatomic organization of autonomic outflow. The peripheral motor portions of the autonomic nervous system are made up of preganglionic and postganglionic neurons. The cell bodies of the preganglionic neurons are located in the visceral efferent (intermediolateral) column of the spinal cord or the homologous motor nuclei of the cranial nerves. Their axons are mostly myelinated, relatively slow-conducting B fibers. The axons synapse on the cell bodies of postganglionic neurons that are located in all cases outside the central nervous system. Each preganglionic axon diverges to an average of 8-9 postganglionic neurons. In this way, autonomic output is diffused. The axons of the postganglionic neurons, mostly unmyelinated C fibers, end on the visceral effectors.

There are many findings that acupuncture act at a spinal (segmental or regional) level. Noxious stimuli from the periphery lead to release peptides in the spinal cord level. These peptides (tachykinins substance P, neurokinin A, calcitonine gene-related peptide, somatostatin etc) modulate the transmition of nociceptive information to the CNS. Using treatment modalities like TENS, Acupuncture and electroacupuncture, we can block the nonociceptive signals, activating descending pain inhibitory systems which act at the level of the specific myelotome. Acupuncture and electroacupuncture have an inhibitory effect on interneurons of the spinal cord (lamina V) and this inhibition is mediated by opiate pain-relieving system.^[17] Also, many laboratories have shown changes in dorsal horn cell activity (gating) during mechanical, chemical and electrical stimulation of somatic and visceral fields. Transcutaneous electrical nerve stimulation (TENS) of somatic areas dicreases the spontaneous and noxiously evoked activity of a majority of dorsal horn neurons (wide-dynamic-range (WDR) cells, High threshold (HT) cells, and high threshold inhibitory (HTi) cells), reducing the perception of pain. ^[18]

This mechanism can be the spinal (regional) action of many analgesic physical methods which we use in daily practice in physiotherapy. Another regional reaction concerns the activation of an area through reflex arches. Those are produced after the stimulation of a peripheral sensory receptor. The stimulus is directed with afferent neural fibers to a sensory or motor nucleus of the spinal cord and a response reaction is produced there.

Analytically:

Viscero-cutaneous reflex or splanchno-fascial reflex. According to that, a functional or organic disease of a viscera causes pain, hypalgesia, tension or irritation to a particular area of the skin. As a general rule, the skin area where pain is projected has, in relation to the painful viscera, common somotomic origin as to the embryo and consequently it is innervated sensorially from the same neurotome of the spinal cord. The skin and the related viscera have the same segmental innervation usually by dorsal roots, spinal nerves and nuclei (referred pain resulting from reflex phenomena). The nociceptive impulses from the affected viscera pass to the dorsal horn and then to anterior horn of spinal cord across interneurons. Visceral afferent nociceptors converge on the same pain projectioeurons as the afferents from the skin.^{[19,20,21,22]}

For example, stimulation of the descending colon with barium chloride is going to create paleness (shrinking of the melanin cells-melanocytes) in an area or 2-3 neurotomes of the specific myelotomes (T9-T12). Moreover, injection of adrenaline 10% to the stomach gastric mucosa, in the gall bladder or in the fascia of the spleen, is going to create skin «shining» at a specific small area of the dermotomes of those organs. ^[23]

Pain in the gall bladder is projected on the skin of the right hypochondrium and on the top part of the right shoulder, a pain related to stomach ulcers corresponding to the 11th thoracic vertebra. The viscero cutaneous reflex we have just described is transmitted via the sympathetic chain. Dissection of the spinal cord does not affect this reflex. It is abolished by the dissection of the sympathetic chain. This reflex is a diagnostic reflex.

Cutaneous visceral reflex . The irritation of a skin point influences functionally the organ by which the cutaneous area is connected according to the neurotomes. Experimentally, to patients with acute angina pectoris the injection of procaine in cutaneous tender points of the anterior thoracic wall brings about fast recession of the precordial pain. Electrical stimulation of the point Futu (L.I. 18) on both sides, provokes analgesia capable of achieving thyroidectomy. This point is found in an area of innervation from the third dorsal cervical spinal nerve. The fascial of the thyroid gland and the above lying skin area where the specific acupuncture point is found are sensorially innervated from the same cervical myelotome. This reflex does not depend on superior brain centres. It follows a clearly neurotomic distribution. Dissection of the visceral nerves abolishes the reflex. Dissection of the vagus nerve does not influence the healing effect. It looks like the myotatic, monosynaptic reflexes. This is a therapeutic reflex.

Viscero-muscular and viscero-visceral or somato-autonomic reflexes are internal reflexes. It is they who interpret muscular contraction and vasocontraction observed in diseases of the internal organs. Sensory fibres from the muscles, the vessels and the affected organ originate from the same myelotome oeighbouring nuclei which are functionally interconnected.^[24] This reflex produses reflex spasm of the skeletal muscle (trigger points of m. pectoralis) during myocardial ischemia. Also, through this reflex we interpret muscular pain during the function of the muscle under conditions of limited blood supply. The sensation of needle insertion into somatic nerve endings in the muscle, ascends with afferent impulses to the anterior hypothalamus. Efferent impulses originate from the same reflex centre of hypothalamus, descend to the cholinergic vasodilator nerve and dilate the blood vessels of the muscle. Dissection of the dorsal spinal roots and that of the visceral nerves abolishes this reflex. A kind of viscero-visceral reflex is activated during the direct excitation of a ganglion by placing a needle deeply in the ganglion or all around the ganglion. As an example I would like to mention point SI 18, which is a meeting point of the head of the arm 3 Yang meridians. This point is being acupunctured during acute pain of the muscular – skeletal system. Why this point is so important in treatment of myoskeletal diseases. It is mentioned that application of local anaesthetics to the mucosa overlying the sphenopalatine ganglion can block pain and is extremely effective on myoskeletal pain especially of the neck and back.

The acupuncture point LE 18 and the sphenopalatine ganglion coincide. In this area, there exists the largest collection of neurons in the head outside the brain itself. It is intimately connected to the trigeminal nerve and nucleus, and the superior cervical sympathetic ganglion. It seems to be the final switch between the body and the brain.

Somatomotors or cutaneo-muscular segmental reflexes. A harmful stimulus to the skin stimulates the axons of sensory fibres of groups III and IV of peripheral nerves. The information of stimulation enters the posterior horns of the spinal cord and is transmitted with the help of intermediate neurons to the motor neurons of the anterior horns. This pathway is polysynaptic and permits on one hand control and on the other deviation of sensory stimulation. Thus, the stimulation of a group of sensory receptors on the muscles, tendons or the skin will cause contraction or relaxation of muscles in the stimulated area (segmental distribution of the reflex). In this manner, by a sensory stimulus (puncture) it is possible to enlist neurons on the same or on the opposite side of the initial stimulation. The usual response to the sensory stimulus is the ipsilateral stimulation of flexors and the inhibition (relaxation) of extensors and the contralateral inhibition of flexors and stimulation of extensors (flexor and cross-extensor reflex).^[27,28] Most rehabilitation treatments by electrophysical agens and, of course, acupuncture, use cutaneo-muscular reflexes to achieve muscle relaxation and to ameliorate the intramuscular blood supply to individual muscles or muscular groups. The selection of the area to be stimulated depends on the target muscle.

Vegetative reflexes are reflexes through the vegetative nervous system (sympathetic and parasympathetic). There is a large number of short and long vegetative reflexes which “close” the nervous circuit in the brain, the spinal cord, in the big nervous ganglia or in smaller peripheral ganglia. There are not only segmental reflexes. Many vegetative reflexes have been describe in medicine. As an example I will mention the segmental and suprasegmental reflexes that are prodused due to local biochemical changes and tissue damage in patiens with acute myocardial ischemia (AMI). This reflex is known as Bezold-Jarich reflex (abnormal vagovagal reflex) and produce severe bradycardia, peripheral vasodilation, severe hypotension and atrioventricular block. These reflexes involves afferents and efferents of both cardiac vagi and cardiac sympathetic nerves which produse sympathosympathetic reflexes. In the AMI patiens exist also suprasegmental reflex responses result from nociceptively induced stimulation of the medullary centers, hypothalamic centers, limbic structures and neuroendocrine function.

According to Gunn, some other common condition of autonomic dysfunction that responce well to acupuncture treatment are the vasomotor, sudomotor, glandular hyperactivity and smooth muscle spasm observing in spondylotic radiculopathy. When pain dissapeare, this autonimic phenomena dissapeare.

Vegetative reflexes can be activated by a) local stimuli, b) general stimuli and c) regional stimuli. From the university of Goteborg ^[30] we have the information that acupuncture may affect the sympathetic system via mechanism at the hypothalamic and brainstem levels and the post-stimulatory sympathetic inhibition that creates, persist for more that 12 hours after acupuncture.

Vegetative reflexes are the clearest evidence of the organisms reaction as an open thermodynamic system. We know very little about these reflexes. The major problem is in describing the connections between the human cortex and the peripheral outflow to smooth muscles, cardiac muscles, secreting glands, sensory organs and vessels. Some organs (heart, gut, spleen, kidney) receive both sympathetic and parasympathetic innervation, while other organs (adrenal, medulla, vascular tissue, skin and muscles) gain only a sympathetic supply. Vegetative nervous system, clinically speaking, is not so autonomus as we believe and seems to be “synergic rather than antagonistic”.^[31,32,33]

SEGMENTAL DISTRIBUTION OF ACU-POINTS

Three big main meridians cross the frontal thoracic and the frontal abdominal wall. The M of the Spleen, Stomach, Kidney and the Conception Vessel Meridian. During their course via abdominal and thoracic wall, this meridians develop 66 ipsilateral points (110 bilateral) Independently of the name of the meridian, if we apply acupuncture to the points found on the thoracic area, we influence the thoracic viscera or their functions, while when we apply acupuncture, using the points developing into meridians of the frontal abdominal wall, we influence the abdominal viscera or their functions. Moreover, all the meridians follow a course towards the middle frontal and the middle dorsal line similar to the segmental distribution of the deep pain that Keelgren [34] has put on a chart after injection of NaCl in the interspinal ligaments of the vertebrae. The dermotomal distribution of the sympathetic fibres coincides with the distribution of the points of acupuncture of the second branch of the Meridian of the urinary bladder.

The same accurate neurotomic distribution of the acupuncture points seems to be preserved by the Urinary Bladder Meridian with the Governing Vessel Meridian. The acupuncture points Lung 1 and 2, Urinary Bladder 13, 14, 15, 41 and Governing Vessel 14, have been used for centuries by acupuncturers for the treatment of lung diseases . All these points concern T2 T4 dermotome of the lungs and they correspond dermotomically to the outlets of the sympathetic chain of the dorsal lung plexus (2nd 4th thoracic sympathetic ganglion). The big bronchial tubes are autonomously innervated by this sympathetic plexus, and also the division of the trachea and all the vessels which transport blood to the bronchial tree. From the same anatomical region start the preganglionic branches of the lower cervical and of the first and the second thoracic ganglion of the sympathetic chain, which are going to form in the depths of the dorsal cervical triangle, the stellar ganglion. The shu-mu technique (synchronus stimulation of abdominal-mu and thoracic, back-shu, points) is a special ancient method that uses the segmental distribution of acu-points to treat deseases of internal abdominal organs.

GENERAL ACTION OF ACUPUNCTURE STIMULATION

Teams of neurophysiologists and research workers on the effect of acupuncture, of electroacupuncture, of electrotherapy and other methods of physical agens have studied the possible mechanisms and the ways of analysing of the peripheral stimulation from the CNS and also the way of answering of the CNS to these stimuli. The integrity of the peripheral nervous system and the spinal cord is considered necessary for the application of acupuncture. It is well known that acupuncture points are «silent» in paraplegic limps (individuals with complete sensory-motor paraplegia) or in experimental animals in which surgical resection of the spinal cord has been effected.

A peripheral stimulus, depending on its quality, may stimulate specific nuclei of the CNS and provoke secretion or qualitative modification of neurotransmitting substances in the blood and the CSF. Besides, each combination of acupuncture points may activates different nerve circuits. This view was based on two experimental results from the University of Peking.^[36]

Experiments on rabbits have shown that following arterial anastomosis of two rabbits (cross circulation technique), analgesia is achieved not only for the rabbit on which acupuncture is applied but also for the rabbit in which the blood of the former circulated through the anastomosis. Furthermore, a CSF transfusion from a cat-donor to which acupuncture analgesia had been applied to another cat-receptor causes analgesia to the donor cat after 10 minutes. Since then, the existence (following acupuncture) of analgesic neurotransmitting substances to the CSF and peripheral blood has been repeatedly confirmed and this clearly shows the activation of central pain control systems (and others) through ancient acu points. Reference to these points is related on one hand to the topographical paradox of the points and on the other to their important therapeutic action. Their particularity has been established both by studies (on experimental animals) and clinically (on patients) and it is well known that randomly selected sham acu-points have an analgesic effect on 28-35% of patients when compared to acu points that have an analgesic effect on 55%-85% of the patients. Papers published from time to time relate to acu points Lung (L) 7, Stomach (S) 36, Large intestine (LI) 4, Spleen (Sp) 6, Large Intestine (LI) 10, Triple Heater (TH) 5, Liver (Liv) 3 and Pericardium (P) 6. The systems activated through these points may be a) opiate endogenous analgesic systems, b) non-opiate systems and c) central sympathetic pain inhibition systems through the reticular formation of the brain.

In recent years, the analgesic action of acupuncture is used for the treatment of cases with acute or chronic pain and less for the surgical analgesia it can offer influencing the chemistry of the descending pain control system. This system consists of four parts: a)spinal system (dorsal horn), b) cortical and diencephalic system, c) mesencephalic (PAG & PVG) system and d) pontine (nucleus raphe magnus) system. Each system uses differente types of endogenous opioid peptides. There is clear evidence of the analgesic action of acupuncture in this field.

This fact excludes suggestion (animals cannot be subject to suggestion), hypnosis, placebo effect (in part) but not stress-induced analgesia.

Pomeranz,^[6] mention the following results in support of the analgesic (endorphinergic) action of acupuncture: Four different opiate antagonists abolish the analgesic action of acupuncture. Naloxone abolishes the analgesic effect. A microinfusion of naloxone or the infusion of endorphin antibodies (to the CNS) abolish the analgesic effect. Mice with a genetically reduced concentration of opiate receptors in the CNS have a poor response to acupuncture. Rabbits with endorphin deficiency do not respond to the acupuncture stimulus. Endorphin levels increase considerably in peripheral blood and in the cerebrospinal fluid during electro-acupuncture while on the contrary their levels in the CNS are reduced. The analgesic effect of acupuncture lasts much more when one impedes the enzymatic degradation of endorphin. The analgesic effect of acupuncture is transmitted through the blood (cross circulation) and the cerebrospinal fluid. The inhibition of pituitary endorphin abolishes the acupuncture effect. An increase of messenger RNA for pro-enkephalin in the brain (pituitary) is observed for 24-48 hours following acupuncture.

About 60% of patients suffering from myofascial pain of the lumbar portion of the spinal cord are considerably relieved after the application of warm compresses (43-51°C) or ultrasound and the improvement of symptoms lasts from 90 minutes to 7 days. On the contrary, the application of electroacupuncture to general acu points relieves the patients for weeks, months or up to 3 years. This was noted (from Price at al.) on 58% of the patients with chronic myofascial pain of the lumbar portion of the spinal cord to which acupuncture was applied . Han suggests that the specific, long-term analgesic effect of acupuncture is due to two factors: a) the activation of a neurogenous serotonin and methencephalin circuit in the upper part of the descending pain inhibition system (in the mid diencephalon). This results in the continuous inhibition (at the level of the spinal cord) and the non-conduction of harmful stimuli from the spinal cord to the CNS, and therefore the non-perception of pain and b) the (peripheral) activation of low-threshold muscular mechanic receptors. In this manner there is an increase of the activity of thick-diameter nerve fibres (pain modulating system) and a long-lasting inhibition of muscular pain. The long-term pain-killing effect of acupuncture is the most difficult point of contemporary theories. Han’s theory (1987 – mesolimbic analgesia system) may be the explanation for one of the acupuncture analgesic mechanisms^[39]. At least, activation of “Diffuse Noxious Inhibitory Controls” (DNIC) triggered by nociceptive peripheral stimuli that activates Aä and C fibers (some formes of acupuncture and moxa) can be an other mechanism of central action of acupuncture and involves complex loops from spinal and supraspinal structures^[40,41]. From these studies came as a result that neurotransmitting substances, opioid and non-opioid substances of spinal cord and CNS are the main co-ordinators of the “stimulation – analysis – response” phenomenon and they are responsible for the generalised internal chemical reactions of the organism that follows an acupuncture treatment.

 

Characteristic of reflector arc of autonomic nervous system

a) Sensory part (Receptors are present in inner organs, walls of blood vessels and lymphatic vessels of skin, muscles. They named interoreceptors. Their stimulus: mechanical, chemical, and temperature irritans. Afferent part of autonomic reflex consists of interoreceptors, dendrites of sensory neurons, which are in autonomic and spinal ganglions.

From interoreceptors afferent informations enter to sensitive neurons, whose body are in autonomic and spinal ganglions. So, in afferent part of autonomic reflex, sensitive information transmit in two ways: 1) from interoreceptors to sensitive neurons of spinal ganglions of dorsal roots of spinal cord; 2) from interoreceptors to sensitive neurons of autonomic ganglions of dorsal, and then to sensitive neurons of spinal ganglion of posterior roots. From spinal ganglions, transmitters of autonomic sensitivity enter in spinal cord. Signal from interoreceptors may enter in brain pass spinal cord. Crossing of afferent signals on interneurons is on spinal’ and bulbar’ level.)

b) Central part (Spinal level. When the neurons enter in spinal cord one part of the afferent fibers interact with segmental interneurons, which interact with preganglionic neurons. This is polysynaptic arc. Part of the afferent fibers end in grey substance of upper segments and medulla oblongata. Part of the afferent fibers lower and connect by synapses with interneurons of lower segments.

 

Supraspinal level. Then the afferent signals go to reticular formation of brein stem. Interaction of afferent visceral and somatic signals activates reticular formation. From reticular formation descending signals transmit to preganglion neurons of arc of autonomic reflex. Ascending signals transmited to mid-brain, dyencephalon and cortex.

c) Efferent part. Peculiarities of mediator transmition in efferent part of autonomic nervous system (scheme):

Transmission at the synaptic junctions between pre- and postganglionic neurons and between the postganglionic neurons and the autonomic effectors is chemically mediated. The principal transmitter agents involved are acetylcholine and norepinephrine, although dopamine is also secreted by intemeurons in the sympathetic ganglia.

Anatomically, the autonomic outflow is divided into 2 components: the sympathetic and parasympathetic divisions of the autonomic nervous system. Sympathetic, or thoracolumbar, division. Motor impulses from the spinal cord to smooth muscles are conveyed over two sets of visceral efferent fibers instead of one, as in somatic motor nerves. A synaptic connection ordinarily is made in a ganglion of the thoracolumbar chain, although this is not necessarily so. There are preganglionic neurons, with cells bodies located in the intermediolateral column of gray matter of the spinal cord and with fibers extending, ordinarily, from the cell body to the autonomic ganglion outside the cord, and a postganglionic neuron. With its cell body located in a ganglion and with its fiber extending to visceral muscle. The preganglionic fiber can extend through the autonomic ganglion to a collateral ganglion, in which case there is a short postganglionic fiber to the organ supplied.

 

PREGANGLIONIC NEURON The cell body of the preganglionic neuron is smaller than that of a motor neuron of the central nervous system. The particles of its Nissle substance are finer and more rounded. The axon emerges from the spinal cord as a part of the motor root of a spinal nerve but soon leaves it to enter the autonomic ganglion. The majority of these axons are myelinated. A group of myelinated fibers presents a white appearance, and so this connection of preganglionic fibers between the spinal nerve and the sympathetic ganglion is called the white branch, or white ramus communicants. When the preganglionic neuron enters the sympathetic ganglion, it makes a synaptic connection with many postganglionic neurons. This arrangement is significant, since it provides for the rapid, widespread response characteristic of the sympathetic system. The thoracic and the first three lumbar nerves are connected with the autonomic chain of ganglia by a white ramus; hence the name thoracolumbar for this division. Cervical ganglia are supplied by preganglionic fibers extending upward from the thoracic nerves through the lateral chains of ganglia. The lower lumbar and sacral ganglia are supplied by fibers extending downward.

 

POSTGANGLIONIC NEURON The postganglionic neuron of the thoracolumbar division has its cell body in a lateral chain ganglion or in a collateral ganglion. The fiber extends to involuntary muscle tissue or to glandular cells; thus the cell bodies of the ganglia of the lateral chain are entirely motor. Postganglionic fibers may take two courses extending beyond the lateral ganglia. They may proceed inward by way of a visceral branch to terminate in the muscles of the viscera, or they may rejoin the spinal nerve by way of the gray root, usually called the gray ramus communicants, and terminate in the involuntary muscles of the peripheral region, such as the muscles in the walls of blood vessels, or in sweat glands of the skin. Since these postganglionic fibers are not myelinated, the nerve appears gray in contrast with the white branch of myelinated preganglionic fibers.

While the white rami are limited to the thoracolumbar region, each spinal nerve is connected with the sympathetic trunk by a gray root. Each spinal nerve, therefore, receives postganglionic fibers.

 

SYMPATHETIC PLEXUSES. The great plexuses of the autonomic system are the cardiac; celiac, or solar; and hypogastric plexus. While these plexuses are regarded as essentially sympathetic, they also receive fibers from the parasympathetic system. The cardiac plexus lies under the arch of the aorta just above the heart. It receives branches from the cervical sympathetic ganglia and from the right and left vagal nerves (parasympathetic) and has a regulatory effect on the heart. The celiac, or solar, plexus is the largest network of cells and fibers of the autonomic system. It lies behind the stomach and is associated with the aorta and the celiac arteries. The ganglia receive the splanchnic nerves from the sympathetic system and branches of the vagus from the parasympathetic system. A blow to this region may slow the heart, reduce the flow of blood to the head, and depress the breathing mechanism.

The hypogastric plexus forms a connection between the celiac plexus above and the two pelvic plexuses below. It is located in front of the fifth lumbar vertebra and continues downward in front of the sacrum, forming the right and left pelvic plexuses. These plexuses supply the organs and blood vessels of the pelvis.

PARASYMPATHETIC, OR CRANIOSACRAL, DIVISION. The craniosacral, or parasympathetic, division of the autonomic nervous system is associated with certain cranial and sacral nerves in which autonomic fibers are incorporated; hence the name craniosacral division (Figure 3). The oculomotor (Hid cranial) nerve, arising in the midbrain, innervates certain voluntary muscles that move the eyeball; in addition, it carries parasympathetic fibers to involuntary muscles within the eyeball. Preganglionic fibers are distributed to the ciliary’s ganglion located behind the eyeball. Postganglionic fibers arising in the ganglion extend to the ciliary’s muscles of the eye and to the sphincter of the pupil. The facial (Vll th cranial), glossopharyngeal (IX th cranial), vagus (X th cranial), and accessory (Xl th cranial) nerves constitute a group of cranial nerves arising from the medulla. Since they also contain parasympathetic fibers, they are a part of the craniosacral division. The vagus supplies the viscera of the thorax and abdomen; this may be the reason why there are no parasympathetic fibers arising from the thoracic or lumbar regions of the cord.

The sacral portion of this system is identified with certain sacral nerves that carry parasympathetic fibers to the pelvic viscera.

 

PREGANGLIONIC AND POSTGANGLIONIC FIBERS. Typically the parasympathetic preganglionic fiber extends from its nucleus in the brain or sacral region of the spinal cord to the organ supplied. The postganglionic fiber is often a very short fiber located within the organ itself. The preganglionic fiber can end in a collateral ganglion, as in the case of preganglionic fibers extending out to the ciliary’s ganglion of the eye. The postganglionic fibers in this case are longer than those incorporated within certain organs.

The parasympathetic system functions as an antagonist of the sympathetic system if an organ is supplied by both systems. If the sympathetic system is the accelerator system, as in the heart, for example, then the parasympathetic system is the inhibitor. Its function in this case is to slow the accelerated heart and thus restore the normal heart rate. Even though it acts as an inhibitor, it does not ordinarily depress the heart rate below normal unless unduly stimulated, as from the action of drugs or pressure on a nerve.

d) Difference between autonimuc and somatic nervous system (1. Nervous centres in autonimuc nervous system are present in mesencephalon, bulbar part of brain, thoraco-lumbal and sacral part of spinal cord, in somatic – diffuse in all sentral nervous system; 2. Efference ways of reflector arc in autonimuc nervous system consist of two neurons, in somatic – of one; 3. In analysing of information in autonimuc nervous system take part ganglions, in somatic – nervous centres; 4. Exit of nervous fibers from central nervous system autonimuc nervous system is mix, in somatic – segmental; 5. Mediators of autonimuc nervous system are acetylcholine, epinephrine, norepinephrine, ATP, serotonine, gistamine, substance P, of somatic – only acethylcholine; 6. Functions of autonimuc nervous system are growth, work of inner organs, supporting of homeostasis of somatic – providing moving reactions of sceletal muscles and sensitive outer stimulus; 7. Effect in autonimuc nervous system may be as excitive, as inhibit, in somatic – only excitive.

Change of functional condition of organs in the case of stimulation of autonomic nerves

 

CRANIAL NERVES THAT CARRY PARASYMPATHETIC FIBERS. If the oculomotor nerve is cut experimentally, the pupil dilates. The parasympathetic fibers within the oculomotor nerve carry nervous impulses that cause the pupil to constrict. Cutting the nerve destroys the balance between parasympathetic and sympathetic innervation. The sympathetic nervous impulses then cause the pupil to dilate. The “drops” placed in the eye for optical examination apparently act in much the same way by blocking the parasympathetic nerve endings.

It has been mentioned that there are four cranial nerves arising from the medulla that carry autonomic fibers and therefore are a part of the craniosacral system. These nerves are the facial glossopharyngeal, vagus, and accessory nerves. The facial nerve includes parasympathetic fibers that are secretary to the lacrimal gland and to the sublingual and submaxillary salivary glands. The lacrimal gland is supplied with postganglionic fibers from the sphenopalatine ganglion. The sublingual and submaxillary salivary glands receive postganglionic fibers arising in the submaxillary ganglion.

Preganglionic fibers in the glossopharyngeal nerve extend outward to the optic ganglion. Postganglionic fibers arise in the otic ganglion and supply the parotid salivary gland. These glands, including the lacrimal, have a double innervation. They derive their sympathetic innervation by way of the superior cervical sympathetic ganglion and carotid plexuses. The action of the two sets of nerves is not clear. Apparently they both contain secretory fibers, but the secretory action of the parasympathetic system seems to be dominant. The vagus nerve contains both motor and visceral afferent fibers. The motor fibers are long preganglionic fibers that extend out to the organ supplied. Very short postganglionic fibers are contained within the organ. Motor fibers are supplied to the larynx, trachea, bronchioles, heart, esophagus, stomach, small intestine, and some parts of the large intestine. Stimulation of the vagus acts as an inhibitor to the heart, causing its rate of beating to slow or to stop. To the muscles of the wall of the digestive tract, branches of the vagus act as accelerator nerves. Peristalsis is increased by parasympathetic stimulation. Parasympathetic fibers to the glands of the digestive tract have regulatory function on secretion, but food content of the stomach or intestine and hormones circulating in the blood can also stimulate secretion.

Parasympathetic fibers from both the right and left vagus nerves enter the great plexuses of the sympathetic system. There is, however, a definite parasympathetic nerve supply to such organs as the pancreas, liver, and kidneys. Nervous stimulation of these organs is, for the most part, merely regulatory. Hormones in the blood normally cause the pancreas and liver to secrete, but stimulation of the vagus increases the flow of pancreatic juice and bile. While sympathetic stimulation of the kidneys by way of the splanchnic nerves results in vasoconstriction and therefore reduced flow of urine, there are many other physiological factors that affect the function of the kidneys. A part of the accessory nerve contains visceral motor and cardiac inhibitory fibers. Certain types of allergy offer examples of overstimulation of the parasympathetic system. Epinephrine can be used to counteract these effects, since it is associated with the action of the sympathetic system.

 

THE SACRAL AUTONOMICS. The sacral portion of the craniosacral system is composed of preganglionic fibers incorporated in the second, third, and fourth sacral nerves. The fibers extend out to the pelvic plexuses, where they enter into close relationship with fibers of the sympathetic system. Parasympathetic fibers innervate the urogenital organs and the distal part of the colon. Postganglionic fibers are considered to be in the organs supplied or in small ganglia located close by. These parasympathetic fibers are motor to the muscles of the distal two-thirds of the colon, to the rectum, and to the urinary bladder. They carry vasodilator impulses to the penis and clitoris. Inhibitory impulses pass to the internal sphincter muscle of the bladder and to the internal sphincter of the anus.

 

PARASYMPATHETIC PLEXUSES. Enteric Plexuses the digestive tube has its own intrinsic nerve supply, consisting of the myenteric plexus, located between the longitudinal and circular muscles and a submucous plexus, located under the mucous layer in the sub mucosa. This part of the nervous system extends the entire length of the digestive tube. It can be assumed that parasympathetic fibers entering the wall of the digestive tract are preganglionic fibers that make synaptic connections with neurons of the enteric system. Sympathetic fibers entering the muscular wall, however, are postganglionic fibers and terminate in the tissues that they supply without making synaptic connections.

The enteric plexuses function in maintaining rhythmic peristaltic movement along the digestive tract. Peristalsis is maintained if both sympathetic and parasympathetic nerve supply is cut. The nerves of the autonomic system, however, exert a regulatory effect.

 

SYMPATHETIC AND PARASYMPATHETIC RELATIONSHIPS. Autonomic effects are usually conditioned by other factors such as the presence of hormones in the bloodstream or by circulatory effects. The secretion of a gland can be depressed by the stimulation of an inhibitor nerve; secretion can also be depressed by vasoconstriction of blood vessels supplying the gland, thus limiting its blood supply. While the sympathetic system can be considered as an accelerator to the heart, the situation is reversed in the case of the action of the autonomic system upon the digestive tract. Here the action of sympathetic nerves depresses peristalsis and the secretion of digestive glands during emotional excitement, while the parasympathetic system, as an accelerator, effects a return to normal. When we speak of the sympathetic and parasympathetic nerves as being antagonistic, we mean this in the sense of antagonistic muscles. The nerves from the sympathetic and parasympathetic systems can produce opposite effects, but they provide a correlated adjustment to meet many physiological conditions. Autonomic effects are not always clearly antagonistic. The accommodation reflex of the eye whereby the lens and iris are adjusted to facilitate clear vision appears to be primarily a parasympathetic function so far as the ciliary’s muscle and the muscles of the iris are concerned. The two sets of muscles of the iris seem to have a synergistic relationship, which causes them to contract or dilate the pupil smoothly in a mild state of opposition to each other. The pupil can also dilate in response to an emotional state such as fear or pain. This is due to stimulation of the sympathetic system.

 

CHEMICAL TRANSMISSION AT AUTONOMIC FUNCTIONS

Transmission at the synaptic junctions between pre- and postganglionic neurons and between the postganglionic neurons and the autonomic effectors is chemically mediated. The principal transmitter agents involved are acetylcholine and norepinephrine, although dopamine is also secreted by interneurons in the sympathetic ganglia.

Chemical Divisions of the Autonomic Nervous System

On the basis of the chemical mediator released, the autonomic nervous system can be divided into cholinergic and noradrenergic divisions. The neurons that are cholinergic are (1) all preganglionic neurons; (2) the anatomically parasympathetic postganglionic neurons; (3) the anatomically sympathetic postganglionic neurons which innervate sweat glands; and (4) the anatomically sympathetic neurons which end on blood vessels in skeletal muscles and produce vasodilatation when stimulated. The remaining postganglionic sympathetic neurons are noradrenergic. The adrenal medulla is essentially a sympathetic ganglion in which the postganglionic cells have lost their axons and become specialized for secretion directly into the bloodstream. The cholinergic preganglionic neurons to these cells have consequently become the secret motor nerve supply of this gland.

 

RESPONSES OF EFFECTOR ORGANS TO AUTONOMIC NERVE IMPULSES

General Principles

On the basis of the chemical mediator released, the autonomic nervous system can be divided into cholinergic and noradrenergic divisions. The neurons that are cholinergic are (1) all preganglionic neurons; (2) the anatomically parasympathetic postganglionic neurons; (3) the anatomically sympathetic postganglionic neurons which innervate sweat glands; and (4) the anatomically sympathetic neurons which end on blood vessels in skeletal muscles and produce vasodilatation when stimulated. The remaining postganglionic sympathetic neurons are noradrenergic. The adrenal medulla is essentially a sympathetic ganglion in which the postganglionic cells have lost their axons and become specialized for secretion directly into the bloodstream. The cholinergic preganglionic neurons to these cells have consequently become the secret motor nerve supply of this gland.

The smooth muscle in the walls of the hollow viscera is generally innervated by both noradrenergic and cholinergic fibers, and activity in one of these systems increases the intrinsic activity of the smooth muscle whereas activity in the other decreases it. However, there is no uniform rule about which system stimulates and which inhibits. In the case of sphincter muscles, both noradrenergic and cholinergic innervations are excitatory, but one supplies the constrictor component of the sphincter and the other the dilator.

There is usually no acetylcholine in the circulating blood, and the effects of localized cholinergic discharge are generally discrete and of short duration because of the high concentration of acetylcholinesterase at cholinergic nerve endings. Norepinephrine spreads farther and has a more prolonged action than acetylcholine. The epinephrine and some of the dopamine come from the adrenal medulla, but much of the norepinephrine diffuses into the bloodstream from norad-renergic nerve endings.

Cholinergic Discharge

In a general way, the functions promoted by activity in the cholinergic division of the autonomic nervous system are those concerned with the vegetative aspects of day-to-day living. For example, cholinergic action favors digestion and absorption of food by increasing the activity of the intestinal musculature, increasing gastric secretion, and relaxing the pyloric sphincter. For this reason, and to contrast it with the ”catabolic” noradrenergic division, the cholinergic division is sometimes called the anabolic nervous system.

Noradrenergic Discharge

The noradrenergic division discharges as a unit in emergency situations. The effects of this discharge are of considerable value in preparing the individual to cope with the emergency, although it is important to avoid the teleologic fallacy involved in the statement that the system discharges in order to do this. For example, noradrenergic discharge relaxes accommodation and dilates the pupils (letting more light into the eyes), accelerates the heartbeat and raises the blood pressure (providing better perfusion of the vital organs and muscles), and constricts the blood vessels of the skin (which limits bleeding from wounds). Noradrenergic discharge also leads to lower thresholds in the reticular formation (reinforcing the alert, aroused state) and elevated blood glucose and free fatty acid levels (supplying more energy). On the basis of effects like these, Cannon called the emergency-induced discharge of the noradrenergic nervous system the ”preparation for flight or fight.”

The emphasis on mass discharge in stressful situations should not obscure the fact that the noradrenergic autonomic fibers also subserve other functions. For example, tonic noradrenergic discharge to the arterioles maintains arterial pressure, and variations in this tonic discharge are the mechanism by which the carotid sinus feedback regulation of blood pressure is effected. In addition, sympathetic discharge is decreased in fasting animals and increased when fasted animals are refed. These changes may explain the decrease in blood pressure and metabolic rate produced by fasting and the opposite changes produced by feeding.

Adrenergic Fibers The terminal filaments of most sympathetic postganglionic neurons produce an adrenalin-like substance and are classified as adrenergic. Sympathetic fibers to sweat glands, blood vessels of the skin, and to the arrestors pylorus muscles are exceptions. These postganglionic fibers enter spinal nerves through the gray rami and reach the skin incorporated in peripheral nerves.

The effects of norepinephrine, in conjunction with epinephrine, can be general and widespread. There is experimental evidence that the chemical substance resulting from excitation of sympathetic postganglionic fibers is carried by the bloodstream and can affect organs remote from the point of origin. It is interesting to note that the sympathetic ganglia and the modularly portion of the adrenal gland have the same embryonic origin. They both arise from neural crest cells. Cholinergic Fibers Parasympathetic fibers also produce a chemical mediating substance. In this case the substance is acetylcholine, which is promptly converted to choline and acetic acid by the action of an enzyme called cholinesterase. Since acetylcholine does not remain in its most active state for any great length of time, it is probable that its effects are entirely local. Unlike norepinephrine, it is probably not carried by the bloodstream.

All preganglionic fibers, whether sympathetic or parasympathetic, have been shown to liberate a cholinergic substance, probably identical with acetylcholine. This means that the transmission of the nervous impulse across the point of synapse between the preganglionic and postganglionic fiber is accomplished by the production of acetylcholine.

As we have indicated, postganglionic sympathetic fibers to the sweat glands and to smooth muscles of the skin are cholinergic. These fibers are carried by peripheral nerves. Voluntary motor nerves to skeletal muscles are also cholinergic. On the basis of chemical transmitter substances it appears that the division of the autonomic system into sympathetic and parasympathetic is somewhat artificial.

MEDULLA OBLONGATA

Control of Respiration, Heart Rate, & Blood Pressure

The medullary centers for the autonomic reflex control of the circulation, heart, and lungs are called the vital centers because damage to them is usually fatal. The afferent fibers to these centers originate in a number of instances in highly specialized visceral receptors. The specialized receptors include not only those of the carotid and aortic sinuses and bodies but also receptor cells that are apparently located in the medulla itself. The motor responses are graded and delicately adjusted and include somatic as well as visceral components.

Other Medullary Autonomic Reflexes

Swallowing, coughing, sneezing, gagging, and vomiting are also reflex responses integrated in the medulla oblongata. Coughing is initiated by irritation of the lining of the respiratory passages. The glottis closes and strong contraction of the respiratory muscles builds up intrapulmonary pressure, whereupon the glottis suddenly opens, causing an explosive discharge of air. Sneezing is a somewhat similar response to irritation of the nasal epithelium. It is initiated by stimulation of pain fibers in the trigeminal nerves.

The limbic system of the brain consists of the hippocampus, the amygdala, the hypothalamus, and the limbic cortex, which all work to regulate emotions and behavior. The limbic system – mainly the hippocampus and amygdala – is also involved in the formation of long-term memory and the functions of the olfactory structures, which are crucial for some organisms’ survival. As a whole, the limbic system encompasses interconnected nuclei and cortical structures found in the telencephalon and diencephalon of the brain that work together to carry out specific functions such as endocrine regulation, establishing of arousal levels, and reinforcement of certain behaviors.

The limbic system is typically divided in two categories: subcortical structures and cortical structures. The cortical regions include the hippocampus, areas of neocortex, the orbital frontal cortex, the subcallosal and cingulate gyrus, and the parahippocampal gyrus. Subcortical portions of the limbic system include the olfactory bulb, hypothalamus, amygdala, septal and thalamic nuclei, the anterior nucleus, and the dorsomedial nucleus. Of these the main regions are the hypothalamus, the amygdala, and the hippocampus.

The hypothalamus is concerned with homeostasis in the body. It lies in the base of the brain, directly above the pituitary gland and below the thalamus. The hypothalamus acts as the primary output node for the limbic system, regulating sexual, endocrine, behavioral, and autonomic functions. In order to perform these essential functions, the hypothalamus requires inputs from the body’s olfactory senses, the viscera, and the retina. It also has internal sensors for temperature, hormone levels (ex. steroids), osmolarity, glucose, and sodium concentration. In a broader sense, the hypothalamus regulates thirst, hunger, body temperature, water balance, and blood pressure, and links the nervous system to the endocrine system via the pituitary gland. Finally, the suprachiasmatic nucleus receives direct retinal input and is responsible for modifying circadian rhythms.

Hypothalamic function is strongly associated with neurosecretion, the release of a secretory substance from the axon terminals of nerve cells in the brain into the circulating blood. During neurosecretion, there occurs throughout the body neurotransmission, the process by which one nerve cell communicates with another via a synapse. These intercellular, transmitted electrical impulses require the secretion of chemicals (neurotransmitters) from the axon of a cell into the synaptic space.

The four maieurotransmitters are epinephrine, norepinephrine, serotonin, and acetylcholine, but recently there have emerged a large number of additional neurotransmitters, some of which actually inhibit neurotransmission (ex. opioids and enkephalins). These neurotransmitters contribute to the network of interconnected neurons that extend from the hypothalamus to key areas such as the cerebral cortex and help direct function to the overall system. Resultantly, intellectual and functional activities as well as external influences such as stress, can be funneled into the hypothalamus and therefore to the endocrine system, from which they may affect the body. In addition to secreting neurotransmitters, the hypothalamus synthesizes and secretes a number of neurohormones, where neurons enter directly into a capillary network to be transported through the hypophyseal-portal circulation to the anterior pituitary gland. These neurohormones are classified as releasing hormones because the major function generally is to stimulate the hormone secretion in the anterior pituitary gland. They consist of simple peptides (chains of amino acids) ranging in size from only three amino acids (thyrotropin-releasing hormone) to 44 amino acids (growth hormone-releasing hormone).

The hypothalamus is divided into two separate areas: the lateral hypothalamus and the ventromedial hypothalamus. The lateral hypothalamus is often called the “hunger center” because it is responsible for the recognition of the necessity for food, water, and sexual desire. It is locate in the anterior and posterior of the hypothalamus. Conversely, the ventromedial hypothalamus is accountable for satiety and satisfaction. It constitutes awareness of satisfaction and in the case of eating, is responsible for the awareness of fullness.

Limited damage to the ventromedial hypothalamus would cause primarily cause obesity because the hypothalamus would be delayed in its response of satiation. Lateral hypothalamic damage, on the other hand, would lead to starvation, as well as other stimulus retardations in the brain. Also, it would affect sexual behavior and arousal as well as other hormone related activities. Severe damage to the hypothalamus would be fatal. The hypothalamus is responsible for the detection of low water in the blood and without this body homeostasis, survival would be impossible.

Hypothalamus Recap:

·                    located in the limbic system below the thalamus

·                    neuroscientists have isolated neural networks within it that perform specific maintenance jobs for the body: body temperature, hunger, moods, sex drive, sleep, thirst

·                    helps control the endocrine system (through the pituitary gland) – contains several types of neurons responsible for releasing different hormones which are released into the blood and capillaries and travel immediately to the anterior lobe of the pituitary: thyrotropin-releasing hormone, gonadotropin-releasing hormone (triggers sexual development), growth-hormone-releasing hormone, corticotropin-releasing hormone (synthesized by the placenta, seems to determine duration of pregnancy), somatostasin (inhibits release of growth hormone and thyroid-stimulating hormone), dopamine (inhibits release of prolactin)

 

·                    Ventromedial – causes one to be aware of satisfaction and is responsible for feeling full when it comes to eating

·                    Lateral – responsible for recognizing the necessity of eating, drinking, and sexual desire

Thalamus

Location: The thalamus is located in the center of the brain, toward the top of the brainstem. It is also the topmost and largest portion of the diencephalon, which is composed of the thalamus and hypothalamus. The diencephalon is above the mesencephalon (midbrain) and below the telencephalon (cerebrum or forebrain). The thalamus is also considered a part of the limbic system, along with the hypothalamus, the amygdala, the hippocampus, and other lesser structures. Made up of grey matter, the thalamus is divided into two lobes in a paired symmetrical structure. These lobes sit on the third ventricle, a fluid-filled cavity, and are joined by the massa intermedia which runs through the ventricle. Most importantly, the thalamus is located in between the cerebral cortex (outer layer of the cerebrum) and the mid-brain.

Function: The thalamus acts as a relay station of movement and sensory information to the cerebral cortex, in addition to receiving information from the cerebral cortex. Axons from all sensory systems, with the exception of olfaction, synapse one last time in the thalamus before they reach the cerebral cortex. The thalamus can divided up into different sets of nuclei which deal with different senses and other various functions. In addition to the relaying of information, the thalamus regulates sleeping and wakeful states, arousal, and level of awareness. When you need to sleep, and you don’t want sensory input entering your cerebral cortex, the thalamus shuts down that pathway.

Damage: Because of the thalamus’s central location, damage can result in insomnia, comas, and the disruption of myriad other senses and connections. A stroke of the thalamus can result in thalamic pain syndrome. Essentially, half of the body becomes chronically hypersensitive to pain – the half opposite the side of the thalamus in which the stroke occurred. This pain takes some time to manifest, and may or may not be permanent. It is very difficult to diagnose, and there isn’t really a form of treatment aside from strong pain medication.

Case Study: In 1975, 21-year-old Karen Ann Quinlan, after eating virtually nothing for two days, drinking gin, and taking Valium, passed out for fifteen minutes without breathing. Her heart was restarted, but she never regained consciousness and fell into a coma. Her parents had to go to the Supreme Court of New Jersey to petition to take her off life support, eventually winning the landmark case. Karen survived for several years after being taken off life support, but eventually died from sepsis stemming from her multiple bedsores. Her autopsy, interestingly, revealed that her cerebrum and spinal cord were fine, and that her thalamus was severely damaged. This alerted doctors to the thalamus’s importance to consciousness, which they had just begun exploring.

Hippocampus

Located in the medial aspect of the temporal lobe, the hippocampus plays a significant role in long-term memory and spatial navigation. Structurally, the hippocampus has the shape of two ram’s horns (Cornu Ammonis), joined at the stems by the hippocampal commissure that crosses the midline under the anterior corpus callosum. The portion of the hippocampus near the base of the temporal lobe is much broader than the part at the top; consequently, cross-sections through the hippocampus can show a variety of shapes, depending on the angle and location of the cut. Because the hippocampus is also considered part of the limbic system, which controls emotion, behavior and olfaction, it is also believed to influence these functions as well.

The first major breakthrough in understanding the hippocampus’ role in memory came when Dr. William Scoville removed the hippocampus of a seizure patient, H.M. After the surgery, H.M. could no longer form new long term episodic memories or recall recent events, only those from years ago. However, H.M’s motor skills did remain intact, even if he did not remember learning them.

Concerning its correlation with memory, in Alzheimer’s disease (loss of memory), the hippocampus is one of the first regions of the brain to suffer. Also, extensive hippocampal damage may lead to amnesia, the inability to form or retaiew memories. There are several types of memory: explicit/declarative is the memory of facts and events, and implicit/non-declarative is the memory of conditioned and emotional responses. Long term memories are stored by being transferred to other areas of the cerebral cortex, and the location of encoding of these memories may be dependent on the type of memory. Someone with hippocampal anomolies may have fully functioning implicit memories and be able to learew skills, but their explicit memories may be severely impaired (so they may not remember having been taught the new skill). However, the hippocampus not only stores memories but also retrieves them. In addition to helping memory, the hippocampus regulates corticosteroid production (Corticosteroids are involved in a wide range of psychologic systems such as stress response, immune response and carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior) and helps to understand spatial relations within the environment.

The hippocampus is one of the first areas to show damage caused by Alzheimer’s, resulting in memory problems and disorientation. Damage to the hippocampus can also cause amnesia (difficulty forming and retaining new memories) and cause you to forget where you have been or where you are going. Any damage, however, will not affect your ability to learn motor skills. Thus, it is logical to assume that someone with limited damage to his/her hippocampus would be able to live as a normal member of society, especially since the hippocampus does not affect “fact memory”.

 

The hypothalamus is part of the brain lying under the thalamus. The stock of the pituitary gland is attached to the hypothalamus.

The main function of the hypothalamus is homeostasis, or maintaining the body’s status quo. Factors such as blood pressure, body temperature, fluid and electrolyte balance, and body weight are held to a precise value called the set-point. Although this set-point can migrate over time, from day to day it is remarkably fixed.

The general functions of the hypothalamus are of extreme importance for the body, such as:

o                    pituitary gland regulation

o                    blood pressure regulation

o                    hunger and salt cravings

o                    feeding

o                    reflexes

o                    thirst

o                    body temperature regulation

o                    hydration

o                    heart rate

o                    bladder function

o                    water preservation

o                    ovarian function

o                    hormonal/neurotransmitter regulation

o                    testicular function

o                    wakefulness

o                    mood & behavioral functions

o                    metabolism

o                    sleep cycles

o                    energy levels

The hypothalamus controls and integrates the overlapping functions of the Endocrine system and the autonomic nervous system.

The hypothalamus links the brain to the hormonal system. The hypothalamus plays a vital role in powerful basic drives for survival such as hunger and thirst and sex and the strong emotions that may accompany them, for instance rage or ecstatic joy. The hypothalamus sends out nerve signals to various muscles often though the autonomic nervous system, for example, in response to a sudden scare, the hypothalamus takes control and tells the adrenal glands to release adrenaline which tells the heart to beat faster, and the skeletal muscles to tense, in the readiness for sudden action, the fight or flight response.

The feeling of hunger which motivates us to eat is generated by the brain’s hypothalamus in response to a range of signals received from the body, including those delivered by various hormones. For example the hormone ghrelin, released by an empty stomach, activates parts of the hypothalamus that make people feel hungry. The hormone leptin, released after eating by the body’s fat stores, causes the hypothalamus to inhibit hunger and create a sense of fullness.

The hormonal surges that occur in puberty are responsible for some of the most dramatic changes that ever occur in the human body. The hypothalamus secretes gondotropic-releasing hormone (GnRH). This triggers the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH), which both acts on the testes or ovaries. LH stimulates Leydig cells to produce testosterone. FSH prompts Sertoli cells to support developing spermatozoa. FSH and LH in turn travel through the bloodstream to trigger the production of the sex hormones primarily estrogen and progesterone from the ovaries and girls in testosterone from the testes in boys. These hormones are responsible for all of the developments underlying puberty in both sexes. The feedback loop reduces GnRH secretion in response to rising levels of testosterone or estrogen.

The In depth functioning of the Hypothalamus

The hypothalamus coordinates many hormonal and behavioral circadian rhythms, complex patterns of neuroendocrine outputs, complex homeostatic mechanisms, and important behaviors. The hypothalamus must therefore respond to many different signals, some of which are generated externally and some internally. The hypothalamus is thus richly connected with many parts of the central nervous system, including the brainstem reticular formation and autonomic zones, the limbic forebrain (particularly the amygdala, septum, diagonal band of Broca, and the olfactory bulbs and the cerebral cortex).

The hypothalamus is responsive to:

o                    Light and dark or Daylight and Nighttime.

o                    Olfactory stimuli, including pheromones

o                    Steroids, including gonad steroids and corticosteroids

o                    Neutrally transmitted information arising in particular from the heart, the stomach, and the reproductive tract

o                    Autonomic inputs

o                    Blood-borne stimuli, including leptin, ghrelin, angiotensin,insulin, pituitary hormones, cytokines, plasma concentrations of glucose and osmolarity etc.

o                    Stress

o                    Invading microorganisms by increasing body temperature, resetting the body’s thermostat upward.

Peptide hormones have important influences upon the hypothalamus, and to do so they must evade the blood-brain barrier. The hypothalamus is bounded in part by specialized brain regions that lack an effective blood-brain barrier; the capillary endothelium at these sites is fenestrated to allow free passage of even large proteins and other molecules. However others are sites at which the brain samples the composition of the blood. Two of these sites, the subfornical organ and the OVLT (organum vasculosum of the lamina terminalis) are so-called circumventricular organs, where neurons are in intimate contact with both blood and Cerebrospinal Fluid. These structures are densely vascularized, and contain osmoreceptive and sodium-receptive neurons which control drinking, vasopressin release, sodium excretion, and sodium appetite. They also contaieurons with receptors for angiotensin, atrial natriuretic factor, endothelin and relaxin, each of which is important in the regulation of fluid and electrolyte balance. Neurons in the OVLT and SFO project to the supraoptic nucleus and paraventricular nucleus, and also to preoptic hypothalamic areas. The circumventricular organs may also be the site of action of interleukins to elicit both fever and ACTH secretion, via effects on paraventricular neurons.

It is not clear how all peptides that influence hypothalamic activity gain the necessary access. In the case of prolactin and leptin, there is evidence of active uptake at the choroidplexus from blood into CSF. Some pituitary hormones have a negative feedback influence upon hypothalamic secretion; for example, growth hormone feeds back on the hypothalamus, but how it enters the brain is not clear. There is also evidence for central actions of prolactin and TSH.

The hypothalamus functions as a type of thermostatfor the body. It sets a desired body temperature, and stimulates either heat production and retention to raise the blood temperature to a higher setting, or sweating and vasodilation to cool the blood to a lower temperature. All fevers result from a raised setting in the hypothalamus; elevated body temperatures due to any other cause are classified as hyperthermia. Rarely, direct damage to the hypothalamus, such as from a stroke, will cause a fever; this is sometimes called a hypothalamic fever. However, it is more common for such damage to cause abnormally low body temperatures.

The hypothalamus contains neurons that react strongly to steroids and glucocorticoids – (the steroid hormones of the adrenal gland, released in response to ACTH). It also contains specialized glucose-sensitive neurons (in the arcuate nucleus and ventromedial hypothalamus), which are important for appetite. The preoptic area contains thermo sensitive neurons; these are important for TRH secretion.

The hypothalamus receives many inputs from the brainstem; notably from the nucleus of the solitary tract, the locus coeruleus, and the ventrolateral medulla. Oxytocin secretion in response to suckling or vaginal-cervical stimulation is mediated by some of these pathways; vasopressin secretion in response to cardiovascular stimuli arising from chemo receptors in the carotid body and aortic arch, and from low-pressure atrial volume receptors, is mediated by others. In the rat, stimulation of the vagina also causes prolactin secretion, and this results in pseudo-pregnancy following an infertile mating. In the rabbit, coitus elicits reflex ovulation. In the sheep, cervical stimulation in the presence of high levels of estrogen can induce maternal in a virgin ewe. These effects are all mediated by the hypothalamus, and the information is carried mainly by spinal pathways that relay in the brainstem. Stimulation of the nipples stimulates release of oxytocin and prolactin and suppresses the release of LH and FSH. Cardiovascular stimuli are carried by the vagus nerve, but the vagus also conveys a variety of visceral information, including for instance signals arising from gastric distension to suppress feeding. Again this information reaches the hypothalamus via relays in the brainstem.

In addition hypothalamic function is responsive to –and regulated by– levels of all three classical monoamine neurotransmitters, i.e. noradrenalin, dopamine and 5-hydroxytryptamine (serotonin), in those tracts from which it receives enervation. For example noradrenergic inputs arising from the locus coeruleus have important regulatory effects upon CRH levels.

The outputs of the hypothalamus can be divided into two categories: neural projections, and endocrine hormones.

Neural projections

Most fiber systems of the hypothalamus run in two ways (bidirectional).

o                    Projections to areas caudal to the hypothalamus go through the medial forebrain bundle, the mammillotegmental tract and the dorsal longitudinal fasciculus.

o                    Projections to areas rostral to the hypothalamus are carried by the mammillothalamic tract, the fornix and terminal stria.

o                    Projections to areas of the sympathetic motor system (lateral horn spinal segments T1-L2/L3) are carried by the hypothalamospinal tract and they activate the sympathetic motor pathway.

Endocrine hormones

The hypothalamus affects the endocrine system and governs emotional behavior, such as anger and sexual activity. Most of the hypothalamic hormones generated are distributed to the pituitary via the hypophyseal portal system.  The hypothalamus maintains homeostasis; this includes a regulation of blood pressure, heart rate, and temperature.

The hypothalamus releases the following hormones:

o                    Thyrotropin-releasing hormone (TRH, TRF) – Which stimulates thyroid stimulating hormone (TSH) release from the pituitary

o                    Prolactin-releasing hormone (PRH) – Which stimulates prolactin release from the pituitary

o                    Dopamine (DA) – which inhibits prolactin release from the pituitary

o                    Grow hormone releasing hormone (GHRH) – stimulates growth hormone (GH) release from the pituitary

o                    Somatostatin (SS) growth hormone inhibiting hormone (GHIH) (SRIF) – which inhibits growth hormone (GH) release from the pituitary and inhibits thyroid stimulating hormone release from the pituitary

o                    Gonadotropin-releasing hormone (GnRH or LHRH) – which stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release from the pituitary

o                    Corticotropin-releasing hormone (CRH or CRF) – which stimulates adrenocortisotropic hormone (ACTH) release from the pituitary

o                    Oxytocin – which causes uterine contractions and lactation

o                    Vasopressin (ADH or AVP) – which increases the permeability to water of the cells of distal tubule and collecting duct in the kidney and thus allows water reabsorption and excretion of concentrated urine

The extreme lateral part of the ventromedial nucleus of the hypothalamus is responsible for the control of food intake. Stimulation of this area causes increased food intake. Bilateral lesion of this area cause complete cessation of food intake. Medial parts of the nucleus have a controlling effect on the lateral part. Bilateral lesion of the medial part of the ventromedial nucleus causes hyperphagia and obesity of the animal. Further lesion of the lateral part of the ventromedial nucleus in the same animal produces complete cessation of food intake.

There are different hypotheses related to this regulation:

o                    Lipostatic hypothesis – this hypothesis holds that adipose tissue produces a humoral signal that is proportionate to the amount of fat and acts on the hypothalamus to decrease food intake and increase energy output. It has been evident that a hormone leptin acts on the hypothalamus to decrease food intake and increase energy output.

o                    Gutpeptide hypothesis – gastrointestinal hormones like Grp, glucagons, CCK and others claimed to inhibit food intake. The food entering the gastrointestinal tract triggers the release of these hormones which acts on the brain to produce satiety. The brain contains both CCK-A and CCK-B receptors.

o                    Glucostatic hypothesis – the activity of the satiety center in the ventromedial nuclei is probably governed by the glucose utilization in the neurons. It has been postulated that when their glucose utilization is low and consequently when the arteriovenous blood glucose difference across them is low, the activity across the neurons decrease. Under these conditions, the activity of the feeding center is unchecked and the individual feels hungry. Food intake is rapidly increased by intraventricular administration of 2-deoxyglucose therefore decreasing glucose utilization in cells.

o                    Thermostatic hypothesis – according to this hypothesis, a decrease in body temperature below a given set point stimulates appetite, while an increase above the set point inhibits appetite.Several hypothalamic nuclei are sexually dimorphic, i.e. there are clear differences in both structure and function between males and females.

Some differences are apparent even in gross neuroanatomy: most notable is the sexually dimorphic nucleus within the preoptic area, which is present only in males. However most of the differences are subtle changes in the connectivity and chemical sensitivity of particular sets of neurons.

The importance of these changes can be recognized by functional differences between males and females. For instance, males of most species prefer the odor and appearance of females over males, which is instrumental in stimulating male sexual behavior. If the sexually dimorphic nucleus is lesioned, this preference for females by males diminishes. Also, the pattern of secretion of growth hormone is sexually dimorphic, and this is one reason why in many species, adult males are much larger than females.

Responses to ovarian hormones

Other striking functional dimorphisms are in the behavioral responses to ovarian hormones of the adult. Males and females respond differently to ovarian steroids, partly because the expression of estrogen-sensitive neurons in the hypothalamus is sexually dimorphic, i.e. estrogen receptors are expressed in different sets of neurons.

Estrogen and progesterone can influence gene expression in particular neurons or induce changes in cell membrane potential and kinase activation, leading to diverse non-genomic cellular functions. Estrogen and progesterone bind to their cognate nuclear hormone receptors, which translocation to the cell nucleus and interact with regions of DNA known as hormone response elements (HREs) or get tethered to another transcription factor’s binding site. Estrogen receptor (ER) has been shown to transactivate other transcription factors in this manner, despite the absence of an estrogen response element (ERE) in the proximal promoter region of the gene. ERs and progesterone receptors (PRs) are generally gene activators, with increased mRNA and subsequent protein synthesis following hormone exposure.

Male and female brains differ in the distribution of estrogen receptors, and this difference is an irreversible consequence of neonatal steroid exposure. Estrogen receptors (and progesterone receptors) are found mainly ieurons in the anterior and mediobasal hypothalamus, notably:

o                    the preoptic area (where LHRH neurons are located)

o                    the periventricular nucleus (where somatostatieurons are located)

o                    the ventromedial hypothalamus (which is important for sexual behavior).

Kallmann syndrome

Kallmann syndrome is a condition characterized by delayed or absent puberty and an impaired sense of smell.

Kallmann syndrome is a hypogonadism (decreased functioning of the glands that produce sex hormones) caused by a deficiency of gonadotropin-releasing hormone (GnRH), which is created by the hypothalamus. Kallmann syndrome is also called hypothalamic hypogonadism, familial hypogonadism with anosmia, and hypogonadotropic hypogonadism, reflecting its disease mechanism.

Kallmann syndrome is a form of tertiary hypogonadism, reflecting that the primary cause of the defect in sex-hormone production lies within the hypothalamus rather than a defect of the pituitary (secondary hypogonadism), testes or ovaries (primary hypogonadism).

Males with hypogonadotropic hypogonadism are often born with an unusually small penis (micropenis) and undescended testes (cryptorchidism). At puberty, most affected individuals do not develop secondary sex characteristics, such as the growth of facial hair and deepening of the voice in males. Affected females usually do not begin menstruating at puberty and have little or no breast development. In some people, puberty is incomplete or delayed.

The features of Kallmann syndrome vary, even among affected people in the same family. Additional signs and symptoms can include a failure of one kidney to develop (unilateral renal agenesis), a cleft lip with or without an opening in the roof of the mouth (a cleft palate), abnormal eye movements, hearing loss, and abnormalities of tooth development. Some affected individuals have a condition called bimanual synkinesis, in which the movements of one hand are mirrored by the other hand. Bimanual synkinesis can make it difficult to do tasks that require the hands to move separately, such as playing a musical instrument.

Under normal conditions, GnRH travels from the hypothalamus to the pituitary gland, where it triggers production and release of LH and FSH. When GnRH is low, the pituitary does not create the normal amount of LH and FSH. The LH and FSH normally increase the production of gonadal steroids; so, when they are low, these steroids will be low as well.

Kallmann syndrome is estimated to affect 1 in 10,000 to 86,000 people and occurs more often in males than in females. Kallmann syndrome 1 is the most common form of the disorder

Researchers have identified four forms of Kallmann syndrome, designated types 1 through 4, which are distinguished by their genetic cause. The four types are each characterized by hypogonadotropic hypogonadism and an impaired sense of smell. Additional features, such as a cleft palate, seem to occur only in types 1 and 2.

Treatment is directed at restoring the deficient hormones. Hormones replacement therapy (HRT)

Males are administered human chorionic gonadotropin (hCG) or testosterone.

Females are treated with estrogen, progestin.

There are a range of different methods for the delivery of HRT, especially for men. The short acting monthly injection is now less widely used in favor of the longer lasting injection, Nebido, which can last from 3 to 6 months depending on the individual. Daily application gels and patches are also available as are implants inserted every 6 months.

Tablets are not thought to be effective for the treatment of Kallmann syndrome due to their low bio-availability once processed by the liver, though this can be overcome by using oil filled capsules which allows the testosterone to reach the blood stream in effective doses.

To induce fertility in males or females, GnRH (aka LHRH) is administered by an infusion pump, or hCG/hMG/FSH/LH combinations are administered through regular injections. Fertility is maintained only during treatment with these hormones. Once fertility treatment stops, it is necessary to revert to the normal hormone-replacement therapy (HRT) of testosterone for men and estrogen, progestin.

 

RELATION OF HYPOTHALAMUS TO AUTONOMIC FUNCTION

Many years ago, Sherrington called the hypothalamus “the head ganglion of the autonomic system.” Stimulation of the hypothalamus produces autonomic responses, but there is little evidence that the hypothalamus is concerned with the regulation of visceral function per se. Rather, the autonomic responses triggered in the hypothalamus are part of more complex phenomena such as rage and other emotions.

“Parasympathetic Center“

Stimulation of the superior anterior hypothalamus occasionally causes contraction of the urinary bladder, a parasympathetic response. Largely on this basis, the statement is often made that there is a “parasympathetic center ” in the anterior hypothalamus. However, bladder contraction can also be elicited by stimulation of other parts of the hypothalamus, and hypothalamic stimulation causes very few other parasympathetic responses. Thus, there is very little evidence that a localized “parasympathetic center” exists. Stimulation of the hypothalamus can cause cardiac arrhythmias, and there is reason to believe that these are due to simultaneous activation of vagal and sympathetic nerves to the heart.

Sympathetic Responses

Stimulation of various parts of the hypothalamus, especially the lateral areas, produces a rise in blood pressure, pupillary dilatation, piloerection, and other signs of diffuse noradrenergic discharge. The stimuli that trigger this pattern of responses in the intact animal are not regulatory impulses from the viscera but emotional stimuli, especially rage and fear. Noradrenergic responses are also triggered as part of the reactions that conserve heat.

Low-voltage electrical stimulation of the middorsal portion of the hypothalamus causes vasodilatation in muscle. Associated vasoconstriction in the skin and elsewhere maintains blood pressure at a fairly constant level. This observation and other evidence support the conclusion that the hypothalamus is a way station on the so-called cholinergic sympathetic vasodilator system, which originates in the cerebral cortex. It may be this system, which is responsible for the dilatation of muscle blood vessels at the start of exercise.

Stimulation of the dorsomedial nuclei and posterior hypothalamic areas produces increased secretion of epinephrine and norepinephrine from the adrenal medulla. Increased adrenal medullary secretion is one of the physical changes associated with rage and fears and may occur when the cholinergic sympathetic vasodilator system is activated. It has been claimed that there are separate hypothalamic centers for the control of epinephrine and norepinephrine secretion. Differential secretion of one or the other of these adrenal medullary catecholamines does occur in certain situations, but the selective increases are small.

RELATION TO SLEEP Lesions of the posterior hypothalamus cause prolonged sleep, and stimulation of the dorsal hypothalamus in conscious animals causes them to go to sleep. These observations have led to consideralable speculation about the existence of ‘sleep centers” a ‘ ‘wakefulness centers ” in the hypothalamus.

RELATION TO CYCLIC PHENOMENA Lesions of the suprachiasmatic nuclei disrupt the circadian rhythm in the secretion of ACTH and melatonin. In addition, these lesions interrupt estrous cycles and activity patterns in laboratory animals. The suprachiasmatic nuclei receive an important input from the eyes via the retinohypothalamic fibers, and it appears that they normally function to entrain various body rhythms to the 24-hour light-dark cycle. There is a prominent serotonergic input from the raphe nuclei to the supra-chiasmatic nuclei, but the exact relation of this input to their function is not known. Feeding & Satiety Centers Hypothalamic regulation of the appetite for food depends primarily upon the interaction of 2 areas: a lateral “feeding center” in the bed nucleus of the medial forebrain bundle at its junction with the pallid hypothalamic fibers, and a medial “satiety center” in the ventromedial nucleus. Stimulation of the feeding center evokes eating behavior in conscious animals, and its destruction causes severe, fatal anorexia in otherwise healthy animals. Stimulation of the ventromedial nucleus causes cessation of eating, whereas lesions in this region cause hyperphagia and, if the food supply is abundant, the syndrome of hypothalamic. Destruction of the feeding center in rats with lesions of the satiety center causes anorexia, which indicates that the satiety center-functions by inhibiting the feeding center.

ANATOMIC CONSIDERATIONS

The term limbic lobe or limbic system is applied to the part of the brain that consists of a rim of cortical tissue around the hilus of the cerebral hemisphere and a group of associated deep structures – the amygdala, the hippocampus, and the septal nuclei. The region was formerly called the rhinencephalon because of its relation to olfaction, but only a small part of it is actually concerned with smell.

LIMBIC FUNCTIONS

Stimulation and ablation experiments indicate that in addition to its role in olfaction, the limbic system is concerned with feeding behavior. Along with the hypothalamus, it is also concerned with sexual behavior, the emotions of rage and fear, and motivation.

Autonomic Responses & Feeding Behavior

Limbic stimulation produces autonomic effects, particularly changes in blood pressure and respiration. These responses are elicited from many limbic structures, and there is little evidence of localization of autonomic responses. This suggests that the autonomic effects are part of more complex phenomena, particularly emotional and behavioral responses. Stimulation of the amygdaloid nuclei causes movements such as chewing and licking and other activities related to feeding. Lesions in the amygdala cause moderate hyperphagia, with indiscriminate ingestion of all kinds of food.

Influence of parasympathetic nervous system on the heart activity

To narcotize a rat and fix it on the preparative table. To make the middle cut on the neck. Find and to separate nervus vagus. Registrate the ECG before and after the electric stimulation of the nerve. Compare the frequency of the heart contraction before and after stimulation of the nerve.

Pilomotor reflex

To make a thermal (ice) or mechanical stimulus of skin in area of trapezoidal muscle. Pay attention on development of anserine skin on the part of the body. Rise of intensive anserine skin on the whole body testifies of increased of irritation of the sympathetic nervous system (slight anserine skin testifies of normal reaction). It is known, that pileous muscles of head and neck are connected with I-III thoracic segments, pileous muscles of hands are connected with IV-VII thoracic segments, pileous muscles of trunk are connected with VIII-IX thoracic segments.

Functional significance of posterior hypothalamus (stereotaxic research)

To determine stereotaxic coordinates of posterior hypothalamus. To narcotize a rat and fix it on a table. Put the identeferentive electrode into the cervic muscles of a rat. The active electrode into the electrodo-holder and lead it into the posterior hypothalamus.

To count a quantity of respiratorical movements during one minute. To make the stimulation and then count a quantity of respiratorical movements once more.

AUTONOMIC CIRCULATORY EFFECTS. Vasoconstriction is a function of the sympathetic system. Although vasodilation may be a function of the parasympathetic system, experimental results are not conclusive. It appears that sympathetic nerves also can include vasodilator fibers. Other factors can influence the blood vessels, such as hormones circulating in the blood stream, the CO2 content of the blood, and temperature.

Sympathetic fibers are conveyed to the blood vessels of the arms and legs by way of the spinal nerves of the central nervous system supplying these regions. Vasoconstriction can be localized or general. In an emergency calling tor quick action, general vasoconstriction causes a rise in blood pressure. At the same time Vasoconstriction may reduce the flow of blood to the digestive tract in a localized area. Muscular exercise requires an increased flow of blood to the skeletal muscles and, therefore, vasodilation of the blood vessels supplying them. Coronary arteries supplying the heart muscle are dilated also. The action of the sympathetic system is supported by epinephrine in the bloodstream. Central Regulation of Visceral Function

The levels of autonomic integration within the central nervous system are arranged, like their somatic counterparts, in a hierarchy. Simple reflexes such as contraction of the full bladder are integrated in the spinal cord. More complex reflexes that regulate respiration and blood pressure are integrated in the medulla oblongata. Those that control papillary responses to light and accommodation are integrated in the midbrain. The complex autonomic mechanisms that maintain the chemical constancy and temperature of the internal environment are integrated in the hypothalamus. The hypothalamus also functions with the limbic system as a until that regulates emotional and instinctual behavior.

Autonomic Reflexes of Spinal cord

Reflex contractions of the full bladder and rectum occur in spinal animals and humans, although the bladder is rarely emptied completely. Hyperactive bladder reflexes can keep the bladder in a shrunken state long enough for hypertrophy and fibrosis of its wall to occur. Blood pressure is generally normal at rest, but the precise feedback regulatioormally supplied by the baroreceptor reflexes is absent and wide swings in pressure are common. Bouts of sweating and blanching of the skin also occur.

Sexual Reflexes of Spinal cord other reflex responses are present in the spinal animal, but in general they are only fragments ol patterns that are integrated in the normal animal into purposeful sequences. The sexual reflexes are example. Coordinated sexual activity depends upon a series of reflexes integrated at many neural levels arc is absent after cord transection. However, genital manipulation in male spinal animals and humans produces erection and even ejaculation. In female spina dogs, vaginal stimulation causes tail deviation and movement of the pelvis into the copulatory position.

Neurosecretion. The hormones of the posterior pituitary gland are synthesized in the cell bodies of neurons in the supraoptic and paraventricular nuclei and transported down the axons of these neurons to the posterior lobe. Some of the neurons make oxytocin and others make vasopressin, and oxytocin-containing and vasopressin-containing cells are found in both nuclei. The neurons also conduct action potentials, and action potentials reaching the endings of the axons trigger release of the hormones by Ca:+-dependent exocytosis. Oxytocin and vasopressin are neural hormones, ie, hormones secreted into the circulation by nerve cells. The term neurosecretion was originally coined to describe the secretion of hormones by neurons.

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Effects of vasopressin because its principal physiologic effect is the retention of water by the kidney, vasopressin is often called the antidiuretic hormone (ADH). It increases the permeability of the collecting ducts of the kidney, so that water enters the hypertonic interstitium of the renal pyramids. The urine becomes concentrated and its volume decreases. The overall effect is therefore retention of water in excess of solute; consequently, the effective osmotic pressure of the body fluids is decreased.

Effect of Oxytocin on the Breast in mammals, an important physiological effect of oxytocin is on the myoepithelial cells, smooth muscle-like cells that line the ducts of the breast. The hormone makes these cells contract, squeezing the milk out of the alveoli of the lactating breast into the large ducts (sinuses) and thence out the nipple. Oxytocin causes contraction of the smooth muscle of the uterus. Feature of Hypothalamic Control Anterior pituitary secretion is controlled by chemical agents carried in the portal hypophyseal vessels from the hypothalamus to the pituitary. These substances have generally been referred to as releasing and inhibiting factors, but they are now commonly called hypophysiotropic hormones. The latter term seems appropriate, since they are secreted into the bloodstream and act at a distance from their site of origin. There are 7 relatively well established hypothalamic releasing and inhibiting hormones: corticotropin-releasing hormone (CRH); thyrotropin-releasing hormone (TRH); growth hormone-releasing hormone (GRH); growth hormone-inhibiting hormone (GIH; also called somatostatin); luteinizing hormone-releasing hormone (LHRH); prolactin-releasing hormone (PRH); and prolactin-inhibiting hormone (PIH) Hypothalamus and temperature regulation Anterior hypothalamus response to heat. Posterior hypothalamus response to cold. Afferents go from cutaneous cold receptors, temperature-sensitive cells in hypothalamus.

References:

1. Review of Medical Physiology // W.F. Ganong. – Twentieth edition, 2001. – P. 217-223, 226-229, 232, 233, 242.

2. Textbook of Medical Physiology // A.C. Guyton, J.E. Hall. – Tenth edition, 2002. – P. 364, 632, 681-684, 697-707, 736.